ChronicStaphylococcus aureusinfection is cured by theory-driven therapy

Abstract

19Staphylococcus aureus (S. aureus) is a challenging human pathogen due to its ability to evade the 20 immune system and resist multidrug antibiotics. These evasive strategies lead to chronic and re-21 current infections. Many studies have documented that during chronic infections Myeloid Derived 22 Suppressor Cells (MDSCs) exert immunosuppressive mechanisms on T cells. A mathematical 23 model explains how the steady state of chronic infection can be disturbed and suggests therapeutic 24 strategies to clear the infection. Model-driven suggestions were tested experimentally and con-25 firmed complete clearance of S. aureus chronic infection. 26 Keywords 27 Myeloid Derived Suppressor Cells, MDSCs, Staphylococcus aureus, chronic infection, mathematical model, 28 therapy, cure, heat-killed cells 29Staphylococcus aureus (S. aureus) is a bacterial human pathogen colonizing 20%-30% of the world pop-30 ulation and responsible for the genesis of nosocomial-acquired and community-acquired bacterial infections. 31 Colonization by S. aureus is typically asymptomatical, implying an equilibrated state between host and bac-32 terium. However, the bacterium can become opportunistic often post-surgery or after implantation of medical 33 devices and can cause skin and soft tissue infections, such as dermatitis, impetigo, and cellulitis 1 , as well as 34 life-threatening conditions like pneumonia and chronic osteomyelitis 2 . Additionally, individuals with immune 35 deficiencies are more susceptible to S. aureus infections. The pathogen constitutes a serious problem in clin-36 ics worldwide because it uses multiple mechanisms to persist in the host. These include strategies of bacterial 37 1 evasion, multi-drug antibiotic resistance, immunosuppression 3 or manipulation of the host's immune regulatory 38 mechanisms, 4;5 which lead to chronic and difficult-to-treat infections. 39Typically, immunosuppression is achieved via regulatory T cells (Tregs), T cell lysis, regulatory B cells 40 (Bregs) 6 , and Myeloid-Derived Suppressor Cells (MDSCs). In the case of S. aureus chronic infections, immuno-41 suppression is not attributed to Bregs, tolerogenic dendritic cells, nor Tregs 7 . Treg-depletion has only a minor 42 effect, whereas T-cell proliferation remains inhibited despite the absence of B220 + and CD11c + cells 7 . Never-43 theless, T-cell suppression in chronically infected mice has been associated with the expansion of monocytic-like 44 (CD11b + Ly6C + Ly6G low phenotype), neutrophilic-like (CD11b + Ly6C low Ly6G + phenotype) and eosonophilic-45 like (CD11b + Ly6C low Ly6G low phenotype) MDSCs 7;8;9;10;11 , affirming the dominant immunosuppressive role of 46 MDSCs during chronic S. aureus infections. 47MDSCs constitute a heterogeneous population of immature myeloid cells, which exert their suppressive 48 effect on T cells by producing reactive oxygen species, nitric oxide, arginase, and inducible nitric oxide syn-49 thase. Significant MDSC expansion and the consequent immunosuppressive effect were reported in long-lasting 50 p...